title: Inhibitory and combinatorial effect of diphyllin, a v-ATPase blocker, on influenza viruses.
abstract: An influenza pandemic poses a serious threat to humans and animals. Conventional treatments against influenza include two classes of pathogen-targeting antivirals: M2 ion channel blockers (such as amantadine) and neuraminidase inhibitors (such as oseltamivir). Examination of the mechanism of influenza viral infection has shown that endosomal acidification plays a major role in facilitating the fusion between viral and endosomal membranes. This pathway has led to investigations on vacuolar ATPase (v-ATPase) activity, whose role as a regulating factor on influenza virus replication has been verified in extensive genome-wide screenings. Blocking v-ATPase activity thus presents the opportunity to interfere with influenza viral infection by preventing the pH-dependent membrane fusion between endosomes and virions. This study aims to apply diphyllin, a natural compound shown to be as a novel v-ATPase inhibitor, as a potential antiviral for various influenza virus strains using cell-based assays. The results show that diphyllin alters cellular susceptibility to influenza viruses through the inhibition of endosomal acidification, thus interfering with downstream virus replication, including that of known drug-resistant strains. In addition, combinatorial treatment of the host-targeting diphyllin with pathogen-targeting therapeutics (oseltamivir and amantadine) demonstrates enhanced antiviral effects and cell protection in vitro.
authors.affiliation: Division of Infectious Disease, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United Sates; Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, United States; School of Veterinary Medicine, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan.
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Chen
authors.forename: Jenna Xiao
authors.initials: JX
authors.lastname: Cheng
authors.forename: Ming-Tsan
authors.initials: MT
authors.lastname: Liu
authors.forename: Kevin
authors.initials: K
authors.lastname: King
authors.forename: Ju-Yi
authors.initials: JY
authors.lastname: Peng
authors.forename: Xin-Quan
authors.initials: XQ
authors.lastname: Zhang
authors.forename: Ching-Ho
authors.initials: CH
authors.lastname: Wang
authors.forename: Sujan
authors.initials: S
authors.lastname: Shresta
authors.forename: Robert T
authors.initials: RT
authors.lastname: Schooley
authors.forename: Yu-Tsueng
authors.initials: YT
authors.lastname: Liu
mesh_terms: D000547:Amantadine / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D011992:Endosomes / Q000821:virology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007251:Influenza, Human / Q000188:drug therapy / Q000201:enzymology* / Q000821:virology; D017705:Lignans / Q000494:pharmacology*; D019684:Magnoliopsida / Q000737:chemistry; D008561:Membrane Fusion / Q000187:drug effects; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000502:physiology; D053139:Oseltamivir / Q000494:pharmacology; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D052117:Benzodioxoles; D004365:Drugs, Chinese Herbal; D004791:Enzyme Inhibitors; D017705:Lignans; D053139:Oseltamivir; D000547:Amantadine; D025262:Vacuolar Proton-Translocating ATPases; C010130:diphyllin
keywords: Amantadine; Diphyllin; Influenza virus; Oseltamivir; Vacuolar ATPase inhibitor